Elucidating Mechanisms of Treatment Relapse for Interferon-Free HCV Therapy

 描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)感染全球1.7亿人，是因发展为肝硬变和肝细胞癌而导致肝脏相关死亡的主要原因。慢性丙型肝炎病毒感染的治疗现在可以通过口服直接作用的抗病毒药物(DAA)的组合来实现，这些药物不需要外源性可注射干扰素(干扰素)就可以实现丙型肝炎病毒的根除。DAA疗法的治疗失败通常是由于治疗后丙型肝炎复发，尽管机制尚不清楚。此外，实现持续病毒学应答(SVR)所需的治疗持续时间(SVR)是根除丙型肝炎的同义词，因人而异，可能受到宿主免疫的影响。该项目的目标是发现丙型肝炎病毒在无干扰素的DAA治疗过程中的宿主免疫相关因素和治疗结果的机制。为此，申请人将利用在治疗过程中收集的临床样本，评估实现SVR的受试者与复发受试者在以下指标上的差异：(1)外周血中的免疫激活和干扰素敏感性，(2)治疗前后的肝脏蛋白质组，利用生物信息学平台进行分析，以及(3)DAA治疗期间淋巴细胞和单核细胞对外部免疫刺激的体外敏感性，询问治疗结束时这种刺激是否可以防止复发。 申请者迈斯纳博士是南卡罗来纳医科大学传染病系的内科科学家，在微生物学和免疫学系担任二次职务。他的长期职业目标是成为一名独立的研究员，研究应对慢性病毒感染的个体间免疫变异机制，以更好地了解疾病进展和对治疗的差异反应。为了促进他向调查独立的过渡，他正在寻求 通过发展组织蛋白质组学、免疫体外研究和生物信息学工具的使用，拓宽了他研究的多学科性质。迈斯纳博士成功的环境来自(1)一个多学科团队，他们在支持该项目所需的指导和专业知识方面有良好的记录，(2)部门和部门的支持，以及有保障的时间来发展内科科学家的职业生涯，(3)可获得一套独特的在不使用干扰素治疗慢性丙型肝炎病毒感染期间收集的临床样本，以及(4)积极参与传染病诊所，为单独感染丙型肝炎病毒或合并感染丙型肝炎病毒和人类免疫缺陷病毒(HIV)的患者提供护理。 在丙型肝炎病毒感染的DAA治疗期间识别治疗复发的相关因素和机制将为活跃的临床领域提供及时的贡献，该领域正在随着新的治疗选择而动态变化。这项培训将使迈斯纳博士能够实现他的长期目标，即成为一名独立的调查员，领导多学科努力，研究宿主对包括丙型肝炎病毒、艾滋病毒和乙肝病毒在内的慢性病毒感染的反应的变异性，目的是了解和改善临床结果。

 DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infects 170 million people worldwide, and is a leading cause of liver-related mortality due to development of cirrhosis and hepatocellular carcinoma. Treatment of chronic HCV infection is now possible with combinations of oral, directly acting antiviral agents (DAAs), which do not require exogenous injectable interferon (IFN) to achieve HCV eradication. Treatment failure with DAA therapy typically occurs due to HCV relapse after treatment, although mechanisms are poorly understood. Furthermore, the necessary duration of treatment required to achieve a sustained virologic response (SVR), synonymous with HCV eradication, differs between people, and may be influenced by host immunity. The goal of this project is to discover host immune correlates and mechanisms of treatment outcome during IFN-free DAA therapy for HCV. To accomplish this, the applicant will utilize clinical samples collected during therapy to assess differences between subjects who achieve SVR versus relapse in markers of (1) immune activation and interferon sensitivity in peripheral blood, (2) the liver proteome before and after treatment, with analysis using bioinformatics platforms, and (3) in vitro sensitivity of lymphocytes and monocytes during DAA therapy to exogenous immune stimulation, asking whether such stimulation at the end of treatment could prevent relapse. The applicant, Dr. Meissner, is a physician-scientist in the Division of Infectious Diseases at the Medical University of South Carolina, with a secondary appointment in the Department of Microbiology and Immunology. His long-term career goal is to become an independent investigator studying mechanisms of inter-individual immune variability in response to chronic viral infections, in order to better understand disease progression and differential response to therapies. To facilitate his transition to investigative independence, he is seeking to broaden the multidisciplinary nature of his investigations by developing expertise in tissue proteomics, in vitro study of immunity, and use of bioinformatic tools. The environment for the success of Dr. Meissner is provided by (1) a multi-disciplinary team with a track record of mentoring and expertise needed to support the project, (2) departmental and divisional support with protected time to develop a career as a physician scientist, (3) availability of a unique set f clinical samples collected during IFN-free therapy for chronic HCV infection, and (4) active clinical participation in an Infectious Diseases clinic providing care to patients infected with HC alone or co-infected with HCV and the human immunodeficiency virus (HIV). Identification of correlates and mechanisms of treatment relapse during DAA therapy for HCV infection will provide timely contributions to an active clinical field that is changing dynamically with new treatment options. This training will enable Dr. Meissner to achieve his long-term goal of becoming an independent investigator leading multidisciplinary efforts to study variability in the host response to chronic viral infections including HCV, HIV, and hepatitis B virus, with the aim of understanding and improving clinical outcomes.